1. Field of the Invention
The invention relates to sterilized monomer and polymer adhesive and sealant compositions, and to their production for industrial and medical uses.
2. State of the Art
Monomer and polymer adhesives are used in both industrial (including household) and medical applications. Included among these adhesives are the 1,1-disubstituted ethylene monomers and polymers, such as the .alpha.-cyanoacrylates. Since the discovery of the adhesive properties of such monomers and polymers, they have found wide use due to the speed with which they cure, the strength of the resulting bond formed, and their relative ease of use. These characteristics have made the .alpha.-cyanoacrylate adhesives the primary choice for numerous applications such as bonding plastics, rubbers, glass, metals, wood, and, more recently, biological tissues.
It is known that monomeric forms of .alpha.-cyanoacrylates are extremely reactive, polymerizing rapidly in the presence of even minute amounts of an initiator, including moisture present in the air or on moist surfaces such as animal tissue. Monomers of .alpha.-cyanoacrylates are anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Once polymerization has been initiated, the cure rate can be very rapid.
Medical applications of 1,1-disubstituted ethylene adhesive compositions include use as an alternate and an adjunct to surgical sutures and staples in wound closure as well as for covering and protecting surface wounds such as lacerations, abrasions, burns, stomatitis, sores, and other open surface wounds. When an adhesive is applied to surfaces to be joined, it is usually applied in its monomeric form, and the resultant polymerization gives rise to the desired adhesive bond. However, at ordinary temperatures, the monomeric form runs when applied to surfaces. As a result, the monomeric adhesive may spread into a wound or along a surface to areas that do not require an adhesive. Therefore, the monomeric form must be controlled in order to prevent undue escape of the adhesive from any given area to which the adhesive is applied. Additionally, sufficient time must be allowed for the monomeric material to polymerize and thus to bring about the desired bonding action. In order to achieve a suitably viscous adhesive, thickening agents can be added to the monomer compositions.
For example, U.S. Pat. No. 3,527,841 to Wicker et al. discloses .alpha.-cyanoacrylate adhesive compositions for both general and surgical uses containing a viscosity modifier that is soluble, after heating, in a wide range of the esters of .alpha.-cyanoacrylic acid. The viscosity modifier is disclosed as poly(lactic acid). After addition of the poly(lactic acid), the composition is sterilized at temperatures up to 150.degree. C. Most of the resulting compositions experienced a decrease in viscosity, presumably resulting from degradation of the thickener by the sterilization process.
U.S. Pat. No. 5,665,817 to Greffet al. discloses alkyl cyanoacrylate compositions suitable for topical application to human skin. The compositions may comprise a suitable amount of a thickening agent to provide a compositional viscosity suitable for certain applications onto human skin. The thickening agent is added to provide a viscosity of from about 2 to 50,000 centipoise at 20.degree. C. The thickening agent employed is any biocompatible material that increases the viscosity of the alkyl cyanoacrylate composition and includes, by way of example, a partial polymer of the alkyl cyanoacrylate, polymethylmethacrylate (PMMA), or other preformed polymers soluble in the alkyl cyanoacrylate. When these solutions are to be stored in applicators suitable for repeated intermittent use, the alkyl cyanoacrylate composition is stored at ambient conditions and is selected to be bacteriostatic. When the selected composition is bacteriostatic, prolonged storage at ambient conditions is without regard to the sterility of the formulation because there is no adverse buildup of bacteria during storage.
U.S. Pat. No. 5,328,687 to Leung et al. also discloses adhesive compositions that may be used for bonding tissue. Compositions comprising .alpha.-cyanoacrylate monomers are preferred. The compositions may further contain adjuvant substances such as thickening agents. Suitable disclosed thickeners include, for example, polycyanoacrylates, polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene. Without specific reference to thickened or unthickened compositions, the '687 patent also mentions that compositions employed in the invention are sterilizable by conventional methods such as by autoclave or by aseptic filtration techniques.
In addition to being viscous, cyanoacrylate compositions for use in many medical applications should be sterile. Due to the importance of achieving and maintaining sterility of these compositions, when an additive, such as a thickening agent, is added to an .alpha.-cyanoacrylate composition, it should be added prior to sterilazation. A problem arises because some thickeners require pretreatment prior to addition to the monomer compositions. U.S. Pat. No. 4,038,345 to O'Sullivan et al. discloses stable cyanoacrylate adhesive compositions having viscosities greater than about 200 centipoise. The compositions are prepared by incorporating, as a thickening agent, a soluble acrylic polymer having a reduced viscosity of about 5 or greater, and a content of free radical polymerization initiator less than 1% by weight. These properties are obtained by subjecting the thickening agent to temperatures of about 140-180.degree. C. for about 30-180 minutes prior to incorporating it in the cyanoacrylate. In one aspect, the '345 patent concerns a process for preparing improved cyanoacrylates which involves heating a conventional polyacrylate thickener at a suitable temperature and for a suitable period of time to reduce its content of free radical polymerization initiators to below about one percent, and increase its reduced viscosity to greater than 5; and dissolving a sufficient amount of the thickener in an ester of 2-cyanoacrylic acid to produce a cyanoacrylate adhesive composition having a viscosity of at least about 500 centipoise. The most highly preferred thickening compound is poly(methylmethacrylate). This thickener is incorporated into the cyanoacrylate monomer by stirring to form a solution. In preparing the thickener, it is maintained at an elevated temperature for a suitable period of time. A satisfactory temperature range is between about 140.degree. and 180.degree. C., and a satisfactory time period is from about 30 to 180 minutes.
However, regardless of the type and number of additives, sterilization of .alpha.-cyanoacrylate adhesive compositions is often difficult to achieve. For example, widely practiced methods of sterilization, such as dry and moist heat sterilization, ionizing radiation, exposure to gas, and sterile filtration, are often not suitable for use with monomeric cyanoacrylate compositions. Problems arise due to polymerization of the monomer during the sterilization process. In many cases, sterilization-induced polymerization is so severe that the resulting product is unusable.
Methods currently used to package and sterilize .alpha.-cyanoacrylate monomer compositions have been developed with the recognition that, to improve efficiency and productivity, the packaging and sterilizing steps should be performed in rapid succession. However, these methods do not provide the desired viscosity of the adhesive compositions. For example, U.S. Pat. No. 5,530,037 to McDonnell et al. discloses that the composition of a sterilezed adhesive would be very limited because necessary additives could not be conveniently added and mixed in a controlled fashion. For example, viscosity modifiers such as polymethylmethacrylate (PMMA) would require heating in a separate vessel to achieve dissolution and this step would destroy the sterility.
Additionally, the problem exists that some thickeners decompose in electron beam and dry heat sterilization. One example of this is poly(2-octylcyanoacrylate), which degrades when exposed to a 160.degree. C. dry heat sterilization cycle or 20-30 kGy of electron beam radiation. In order to confirm this, formulations were prepared using poly(2-octylcyanoacrylate) as a thickening agent and 2-octylcyanoacetate as the non-polymerizable medium. The data in Table I confirms that poly(2-octylcyanoacrylate) is unstable under current dry heat and electron beam sterilization methods.
TABLE I Poly(2-octylcyanoacrylate)(P2OCA) P2OCA Thickened Formulations Viscosity (cps) 160.degree. C. Run Dry % % % # Control Heat Change 20 kGy Change 30 kGy Change 1 117 31 -73.2 37 -68.3 31 -73.5 2 138 62 -55.2 46 -67.0 37 -73.2 3 133 48 -64.2 36 -73.0 32 -73.9 4 139 63 -54.7 43 -69.1 37 -73.4 5 139 64 -53.9 40 -71.2 35 -74.8 6 143 57 -60.1 45 -68.3 38 -73.4 7 142 70 -50.4 40 -71.6 33 -76.8 8 142 67 -53.1 44 -68.8 38 -73.2
Visocosity is used as a measure of stability since a stable formulation should have a viscosity change of zero after sterilization. If the viscosity decreases, this indicates degradation of the thickener (here, poly(2-octylcyanoacrylate)).
Many other thickeners are also subject to decomposition under sterilization conditions. Such instability is particularly common in compositions in which the adhesive monomers are stabilized by the presence of acids, because those acids frequently destabilize the thickening polymers also present in the composition. For example, lactic acid-caprolactone copolymers in a stabilized 2-octylcyanoacrylate monomer composition tend to decompose when such a composition is subjected to dry heat sterilization conditions, causing the thickener to lose thickening effect. Such acid stabilizers are, however, present in many cyanoacrylate adhesive compositions.
In addition, aseptic filtration is a known method for sterilizing cyanoacrylate compositions before they are placed into a container. However, aseptic filtration is very difficult with high viscosity compositions, and involves prohibitively expensive technology.
Thus, a need exists for improved monomer cyanoacrylate adhesive compositions, especially for medical uses, having a greater viscosity without sacrificing the performance of the adhesive. The need further exists for a sterilized monomeric adhesive composition that does not require pre-treatment of the thickener prior to its addition to the monomeric adhesive. Additionally, the need exists for a sterilized monomeric adhesive in which the thickener has not decomposed during sterilization.